Using a murine cardiac arrest model, we will define oxidant-mediated apoptosis in the post-resuscitation phase of cardiac arrest. Our proposal extends work by others and our own cellular studies that implicate oxidant-mediated apoptosis as a cause of significant cell and organ injury after reperfusion following ischemia. This post resuscitation injury may be particularly important following the global ischemia of cardiac arrest, after which almost 90% of patients go on to die hours to days later even after an initially "successful" immediate resuscitation. The Emergency Resuscitation Center at the University of Chicago has developed a translational murine model of cardiac arrest which reflects this post-resuscitation injury, demonstrates activation of cellular apoptotic markers and oxidant-mediated transcriptional changes 18 hours after cardiac arrest, and will allow use of genetically altered animals to further define post-resuscitation processes. Specifically, we aim to use this new model to define the role of intrinsic and extrinsic apoptotic pathways in key organs during post-resuscitation injury and death following murine cardiac arrest. We will test the contribution of the intrinsic apoptotic pathway during cardiac arrest by treatment of mice with a caspase 9 inhibitor, and by using Bcl-2 and Bax knockout mice, which exhibit alterations in apoptotic function. We will test the contribution of the extrinsic apoptotic pathway by studying cardiac arrest in mice treated with a caspase 8 inhibitor, and by using Fas-deficient and Fas ligand-deficient mice. We also aim to define the contribution of oxidants to the sequence of apoptosis. To do this, we will study cardiac arrest while treating mice with antioxidants and by using superoxide dismutase (SOD1) transgenic mice, both alterations known to be protective during ischemia. Outcomes in these studies will include multiple markers of apoptosis, oxidant generation, hemodynamics, neurologic function, cardiac function and survival to 7 days. The highlight of this translational model is its ability to provide insights into integrative physiology, test for similarities and differences between organs exposed to the same ischemic insult, and test for the remote effects that one organ may have on distant organs. Finally we will ask whether antiapoptotic and antioxidant therapies can improve survival and function after cardiac arrest, a leading cause of death in our society.